Limits...
Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes.

Taparra K, Tran PT, Zachara NE - Front Oncol (2016)

Bottom Line: The HBP utilizes glycolytic intermediates to generate the metabolite UDP-GlcNAc.This and other charged nucleotide sugars serve as the basis for biosynthesis of glycoproteins and other glycoconjugates.Altered protein glycosylation downstream of the HBP is well positioned to mediate many cellular changes associated with EMT including cell-cell adhesion, responsiveness to growth factors, immune system evasion, and signal transduction programs.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

ABSTRACT
The epithelial-mesenchymal transition (EMT) is a highly conserved program necessary for orchestrating distant cell migration during embryonic development. Multiple studies in cancer have demonstrated a critical role for EMT during the initial stages of tumorigenesis and later during tumor invasion. Transcription factors (TFs) such as SNAIL, TWIST, and ZEB are master EMT regulators that are aberrantly overexpressed in many malignancies. Recent evidence correlates EMT-related transcriptomic alterations with metabolic reprograming in cancer. Metabolic alterations may allow cancer to adapt to environmental stressors, supporting the irregular macromolecular demand of rapid proliferation. One potential metabolic pathway of increasing importance is the hexosamine biosynthesis pathway (HBP). The HBP utilizes glycolytic intermediates to generate the metabolite UDP-GlcNAc. This and other charged nucleotide sugars serve as the basis for biosynthesis of glycoproteins and other glycoconjugates. Recent reports in the field of glycobiology have cultivated great curiosity within the cancer research community. However, specific mechanistic relationships between the HBP and fundamental pathways of cancer, such as EMT, have yet to be elucidated. Altered protein glycosylation downstream of the HBP is well positioned to mediate many cellular changes associated with EMT including cell-cell adhesion, responsiveness to growth factors, immune system evasion, and signal transduction programs. Here, we outline some of the basics of the HBP and putative roles the HBP may have in driving EMT-related cancer processes. With novel appreciation of the HBP's connection to EMT, we hope to illuminate the potential for new therapeutic targets of cancer.

No MeSH data available.


Related in: MedlinePlus

Molecular pathways and targets of the epithelial–mesenchymal transition. (A) (1) One of the most well characterized EMT-inducing pathways is the transforming growth factor-β (TGF-β) family receptors capable of inducing PI3K–AKT, ERK MAPK, p38 MAPK, and JUN N-terminal kinase (JNK) pathways (activating pathways in blue; inactivating pathways in red). (2) The RAS–RAF–MEK–ERK MAPK pathway lies downstream of a number of growth factor activated receptor tyrosine kinases (RTKs) and activates a number of major EMT transcription factors (TFs). (3) Integrin signaling can have a multipronged effect on EMT by both interrupting critical epithelial adhesion molecules (e.g., E-cadherin) and antagonizing GSK3-β via the integrin-linked kinase (ILK)-AKT signaling, thus promoting EMT. (4) WNT signaling can also interfere with GSK3-β, thus stabilizing β-catenin to promote EMT transcriptional programs in cooperation with lymphoid enhancer-binding factor 1 (LEF1) and T-cell factor (TCF). (5) The Hedgehog (HH)-glioma 1 (GLI1) and (6) NOTCH pathway both can promote transcription of the EMT regulators. (7) Recently, a number of inflammatory pathways downstream of interleukin (IL) signaling (e.g., IL-6) have demonstrated the activation of the Janus-kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, which in turn promotes EMT transcription factors. (8) Hypoxia is capable of activating a number of key components of EMT through the hypoxia-induced factor 1 (HIF1α). (B) Downstream of these signal transduction pathways leading to EMT are a variety of transcription factors with the ability to alter epithelial gene expression. As an epithelial plasticity program, many of the target genes altered include adhesion molecules. Known glycosylated proteins involved with EMT are denoted with an asterisk (*).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834358&req=5

Figure 1: Molecular pathways and targets of the epithelial–mesenchymal transition. (A) (1) One of the most well characterized EMT-inducing pathways is the transforming growth factor-β (TGF-β) family receptors capable of inducing PI3K–AKT, ERK MAPK, p38 MAPK, and JUN N-terminal kinase (JNK) pathways (activating pathways in blue; inactivating pathways in red). (2) The RAS–RAF–MEK–ERK MAPK pathway lies downstream of a number of growth factor activated receptor tyrosine kinases (RTKs) and activates a number of major EMT transcription factors (TFs). (3) Integrin signaling can have a multipronged effect on EMT by both interrupting critical epithelial adhesion molecules (e.g., E-cadherin) and antagonizing GSK3-β via the integrin-linked kinase (ILK)-AKT signaling, thus promoting EMT. (4) WNT signaling can also interfere with GSK3-β, thus stabilizing β-catenin to promote EMT transcriptional programs in cooperation with lymphoid enhancer-binding factor 1 (LEF1) and T-cell factor (TCF). (5) The Hedgehog (HH)-glioma 1 (GLI1) and (6) NOTCH pathway both can promote transcription of the EMT regulators. (7) Recently, a number of inflammatory pathways downstream of interleukin (IL) signaling (e.g., IL-6) have demonstrated the activation of the Janus-kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, which in turn promotes EMT transcription factors. (8) Hypoxia is capable of activating a number of key components of EMT through the hypoxia-induced factor 1 (HIF1α). (B) Downstream of these signal transduction pathways leading to EMT are a variety of transcription factors with the ability to alter epithelial gene expression. As an epithelial plasticity program, many of the target genes altered include adhesion molecules. Known glycosylated proteins involved with EMT are denoted with an asterisk (*).

Mentions: Epithelial–mesenchymal transition is an essential epithelial plasticity program deployed during development (23, 24), wound healing (25–27), and stem cell maintenance (28–31). The major characteristics of EMT include loss of cellular adhesion, reorganization of cytoskeleton, loss of cellular polarity, and a switch from epithelial to mesenchymal gene expression (18). Many of these EMT pathways are activated by extracellular signaling, highlighting the importance of the tumor microenvironment for the induction of EMT. Figure 1A outlines eight critical EMT-activating pathways: TGF-β, receptor tyrosine kinases (RTKs), integrin, WNT, NOTCH, Hedgehog (HH), hypoxia inducible factor 1α (HIF1α), and JAK/STAT.


Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes.

Taparra K, Tran PT, Zachara NE - Front Oncol (2016)

Molecular pathways and targets of the epithelial–mesenchymal transition. (A) (1) One of the most well characterized EMT-inducing pathways is the transforming growth factor-β (TGF-β) family receptors capable of inducing PI3K–AKT, ERK MAPK, p38 MAPK, and JUN N-terminal kinase (JNK) pathways (activating pathways in blue; inactivating pathways in red). (2) The RAS–RAF–MEK–ERK MAPK pathway lies downstream of a number of growth factor activated receptor tyrosine kinases (RTKs) and activates a number of major EMT transcription factors (TFs). (3) Integrin signaling can have a multipronged effect on EMT by both interrupting critical epithelial adhesion molecules (e.g., E-cadherin) and antagonizing GSK3-β via the integrin-linked kinase (ILK)-AKT signaling, thus promoting EMT. (4) WNT signaling can also interfere with GSK3-β, thus stabilizing β-catenin to promote EMT transcriptional programs in cooperation with lymphoid enhancer-binding factor 1 (LEF1) and T-cell factor (TCF). (5) The Hedgehog (HH)-glioma 1 (GLI1) and (6) NOTCH pathway both can promote transcription of the EMT regulators. (7) Recently, a number of inflammatory pathways downstream of interleukin (IL) signaling (e.g., IL-6) have demonstrated the activation of the Janus-kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, which in turn promotes EMT transcription factors. (8) Hypoxia is capable of activating a number of key components of EMT through the hypoxia-induced factor 1 (HIF1α). (B) Downstream of these signal transduction pathways leading to EMT are a variety of transcription factors with the ability to alter epithelial gene expression. As an epithelial plasticity program, many of the target genes altered include adhesion molecules. Known glycosylated proteins involved with EMT are denoted with an asterisk (*).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834358&req=5

Figure 1: Molecular pathways and targets of the epithelial–mesenchymal transition. (A) (1) One of the most well characterized EMT-inducing pathways is the transforming growth factor-β (TGF-β) family receptors capable of inducing PI3K–AKT, ERK MAPK, p38 MAPK, and JUN N-terminal kinase (JNK) pathways (activating pathways in blue; inactivating pathways in red). (2) The RAS–RAF–MEK–ERK MAPK pathway lies downstream of a number of growth factor activated receptor tyrosine kinases (RTKs) and activates a number of major EMT transcription factors (TFs). (3) Integrin signaling can have a multipronged effect on EMT by both interrupting critical epithelial adhesion molecules (e.g., E-cadherin) and antagonizing GSK3-β via the integrin-linked kinase (ILK)-AKT signaling, thus promoting EMT. (4) WNT signaling can also interfere with GSK3-β, thus stabilizing β-catenin to promote EMT transcriptional programs in cooperation with lymphoid enhancer-binding factor 1 (LEF1) and T-cell factor (TCF). (5) The Hedgehog (HH)-glioma 1 (GLI1) and (6) NOTCH pathway both can promote transcription of the EMT regulators. (7) Recently, a number of inflammatory pathways downstream of interleukin (IL) signaling (e.g., IL-6) have demonstrated the activation of the Janus-kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, which in turn promotes EMT transcription factors. (8) Hypoxia is capable of activating a number of key components of EMT through the hypoxia-induced factor 1 (HIF1α). (B) Downstream of these signal transduction pathways leading to EMT are a variety of transcription factors with the ability to alter epithelial gene expression. As an epithelial plasticity program, many of the target genes altered include adhesion molecules. Known glycosylated proteins involved with EMT are denoted with an asterisk (*).
Mentions: Epithelial–mesenchymal transition is an essential epithelial plasticity program deployed during development (23, 24), wound healing (25–27), and stem cell maintenance (28–31). The major characteristics of EMT include loss of cellular adhesion, reorganization of cytoskeleton, loss of cellular polarity, and a switch from epithelial to mesenchymal gene expression (18). Many of these EMT pathways are activated by extracellular signaling, highlighting the importance of the tumor microenvironment for the induction of EMT. Figure 1A outlines eight critical EMT-activating pathways: TGF-β, receptor tyrosine kinases (RTKs), integrin, WNT, NOTCH, Hedgehog (HH), hypoxia inducible factor 1α (HIF1α), and JAK/STAT.

Bottom Line: The HBP utilizes glycolytic intermediates to generate the metabolite UDP-GlcNAc.This and other charged nucleotide sugars serve as the basis for biosynthesis of glycoproteins and other glycoconjugates.Altered protein glycosylation downstream of the HBP is well positioned to mediate many cellular changes associated with EMT including cell-cell adhesion, responsiveness to growth factors, immune system evasion, and signal transduction programs.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

ABSTRACT
The epithelial-mesenchymal transition (EMT) is a highly conserved program necessary for orchestrating distant cell migration during embryonic development. Multiple studies in cancer have demonstrated a critical role for EMT during the initial stages of tumorigenesis and later during tumor invasion. Transcription factors (TFs) such as SNAIL, TWIST, and ZEB are master EMT regulators that are aberrantly overexpressed in many malignancies. Recent evidence correlates EMT-related transcriptomic alterations with metabolic reprograming in cancer. Metabolic alterations may allow cancer to adapt to environmental stressors, supporting the irregular macromolecular demand of rapid proliferation. One potential metabolic pathway of increasing importance is the hexosamine biosynthesis pathway (HBP). The HBP utilizes glycolytic intermediates to generate the metabolite UDP-GlcNAc. This and other charged nucleotide sugars serve as the basis for biosynthesis of glycoproteins and other glycoconjugates. Recent reports in the field of glycobiology have cultivated great curiosity within the cancer research community. However, specific mechanistic relationships between the HBP and fundamental pathways of cancer, such as EMT, have yet to be elucidated. Altered protein glycosylation downstream of the HBP is well positioned to mediate many cellular changes associated with EMT including cell-cell adhesion, responsiveness to growth factors, immune system evasion, and signal transduction programs. Here, we outline some of the basics of the HBP and putative roles the HBP may have in driving EMT-related cancer processes. With novel appreciation of the HBP's connection to EMT, we hope to illuminate the potential for new therapeutic targets of cancer.

No MeSH data available.


Related in: MedlinePlus